US2005070494A1PendingUtilityA1

Transforming growth factor-beta response element decoys and methods

34
Priority: May 14, 2003Filed: May 14, 2004Published: Mar 31, 2005
Est. expiryMay 14, 2023(expired)· nominal 20-yr term from priority
Inventors:Kenneth CutroneoJen-Fu Chiu
A61P 35/00C07H 21/00C12N 15/1136C12N 2310/13A61P 1/16C12N 2310/315A61K 38/00
34
PatentIndex Score
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Claims

Abstract

Products and methods for treating fibrosis, liver cirrhosis and cancer, and for altering or modulating the expression of genes regulated by transforming growth factor—beta (TGF-β) are provided. Nucleic acid molecules comprising TGF-response elements have a high affinity for transcription factors modulated by TGF-β. In one embodiment, nucleic acid molecules comprising TGF-β response elements can be used as decoys to alter the expression of genes regulated by TGF-β (e.g., proα1(I) collagen) and treat a variety of conditions related to aberrant expression of TGF-β regulated genes (e.g., fibrosis, liver cirrhosis, tumors, cancers).

Claims

exact text as granted — not AI-modified
1 . An isolated nucleic acid molecule comprising SEQ ID NO: 1, wherein the nucleic acid molecule is capable of binding a transcription factor modulated by TGF-β.  
     
     
         2 . The isolated nucleic acid of  claim 1 , wherein said nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         3 . The isolated nucleic acid of  claim 1 , wherein the TGF-β response elements are linked by one or more bases.  
     
     
         4 . An isolated nucleic acid molecule comprising SEQ ID NO: 2, wherein the nucleic acid molecule is capable of binding a transcription factor modulated by TGF-β.  
     
     
         5 . The isolated nucleic acid of  claim 4 , wherein said nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         6 . The isolated nucleic acid of  claim 4 , wherein said nucleic acid molecule comprises two or more TGF- a response elements.  
     
     
         7 . An isolated nucleic acid molecule comprising a derivative of SEQ ID NO: 1, wherein the nucleic acid molecule is capable of binding a transcription factor modulated by TGF-β.  
     
     
         8 . An isolated nucleic acid molecule comprising a derivative of SEQ ID NO: 2, wherein the nucleic acid molecule is capable of binding a transcription factor modulated by TGF-β.  
     
     
         9 . A cell comprising the nucleic acid molecule of  claim 1  or  claim 4 .  
     
     
         10 . A method of regulating expression of a gene comprising a TGF-β response element comprising administering to a cell a nucleic acid molecule comprising SEQ ID NO: 1.  
     
     
         11 . The method of  claim 10 , wherein the nucleic acid molecule is capable of binding to a transcription factor that is modulated by TGF-β.  
     
     
         12 . The method of  claim 10 , wherein the nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         13 . The method of  claim 10 , wherein the double-stranded nucleic acid molecule comprises two or more TGF-β response elements.  
     
     
         14 . A method of regulating expression of a gene comprising a TGF-β response element comprising administering to a cell a nucleic acid molecule comprising SEQ ID NO: 2.  
     
     
         15 . The method of  claim 14 , wherein the nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         16 . The method of  claim 14 , wherein the double-stranded nucleic acid molecule comprises two or more TGF-β response elements.  
     
     
         17 . A method of regulating expression of a gene comprising a TGF-β response element comprising administering to a cell a derivative of a nucleic acid molecule comprising SEQ ID NO: 1.  
     
     
         18 . A method of regulating expression of a gene comprising a TGF-β response element comprising administering to a cell a derivative of a nucleic acid molecule comprising SEQ ID NO: 2.  
     
     
         19 . A method of treating or preventing liver cirrhosis or tissue fibrosis in a human comprising administering to said human a nucleic acid molecule comprising SEQ ID NO: 1.  
     
     
         20 . The method of  claim 19 , wherein the nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         21 . The method of  claim 19 , wherein the nucleic acid molecule comprises two or more TGF-β response elements.  
     
     
         22 . The method of  claim 19 , wherein said administration is by intravenous infusion.  
     
     
         23 . The method of  claim 19 , wherein the nucleic acid molecule is administered for a period of 2 to 13 days.  
     
     
         24 . The method of  claim 19 , wherein the nucleic acid molecule is administered for a period of 14 to 28 days.  
     
     
         25 . The method of  claim 19 , further comprising administering about 0.01 to about 10 mg/kg/day of the nucleic acid molecule.  
     
     
         26 . The method of  claim 19 , further comprising administering about 10 to about 50 mg/kg/day of the nucleic acid molecule.  
     
     
         27 . A method of treating or preventing liver cirrhosis or tissue fibrosis in a human comprising administering to said human, in which such treatment or prevention is desired, a nucleic acid molecule comprising SEQ ID NO: 2.  
     
     
         28 . The method of  claim 27 , wherein the nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         29 . The method of  claim 27 , wherein the nucleic acid molecule comprises two or more TGF-β response elements.  
     
     
         30 . The method of  claim 27 , wherein said administration is intravenous infusion.  
     
     
         31 . The method of  claim 27 , wherein the nucleic acid molecule is administered for a period of 2 to 13 days.  
     
     
         32 . The method of  claim 27 , wherein the nucleic acid molecule is administered for a period of 14 to 28 days.  
     
     
         33 . The method of  claim 27 , further comprising administering about 0.01 to about 10 mg/kg/day of the nucleic acid molecule.  
     
     
         34 . The method of  claim 27 , further comprising administering about 10 to about 50 mg/kg/day of the nucleic acid molecule.  
     
     
         35 . A pharmaceutical composition comprising a nucleic acid molecule comprising SEQ ID NO: 1 and a pharmaceutically acceptable carrier.  
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein the nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein the nucleic acid molecule comprises two or more TGF-β response element sequences.  
     
     
         38 . A pharmaceutical composition comprising a nucleic acid molecule comprising SEQ ID NO: 2 and a pharmaceutically acceptable carrier.  
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the nucleic acid molecule is a double stranded phosphorothioate nucleic acid molecule.  
     
     
         40 . The pharmaceutical composition of  claim 38 , wherein the nucleic acid molecule comprises two or more TGF-β response element sequences.  
     
     
         41 . A pharmaceutical composition comprising a derivative of a nucleic acid molecule comprising SEQ ID NO: 1 and a pharmaceutically acceptable carrier.  
     
     
         42 . A pharmaceutical composition comprising a derivative of a nucleic acid molecule comprising SEQ ID NO: 2 and a pharmaceutically acceptable carrier.  
     
     
         43 . A kit comprising a nucleic acid molecule comprising SEQ ID NO: 1 or SEQ ID NO: 2.

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